ABSTRACT ? Project 1: Human Gut Microbiome, Metabolome and AD Phenotypes Accumulating evidence characterizes Alzheimer?s disease (AD) as a metabolic disorder with several biochemical perturbations identified. Genetic factors, gut bacteria, diet, lifestyle, and environmental exposures all contribute to human metabolism and its dysregulation in disease states including AD. Many bioactive metabolites, such as vitamins, short-chain fatty acids, and neurotransmitters (e.g., GABA, dopamine, norepinephrine serotonin), are produced by the gut bacteria and thus can modulate brain function. Bidirectional biochemical communication between the brain and the gut may contribute to neurodegenerative and psychiatric diseases including depression and neurodegenerative diseases. Recently, a role for the gut microbiome in the etiology of Parkinson?s disease was highlighted by Co-PI Mazmanian. Further, we show distinct profiles in microbial metabolites in brains of AD patients, suggesting that changes to the human microbiome alter the metabolic output of gut bacteria to send potentially disease-modifying chemicals into the brain that may contribute to pathophysiology. In this proposal, we seek a deeper understanding of the role of the gut microbiome in AD pathogenesis and use powerful metagenomics and metabolomics tools to define biochemical axis of communication between the gut and brain. To implement this project we will build on large initiatives and established infrastructures including: The American Gut Project and Human Microbiome Project (led by Co-PI Knight), the AD Metabolomics Consortium (led by Co-PI Kaddurah-Daouk), AD Research Centers (ADRCs), National Centralized Repository for AD and Related Dementias (NCRAD), The National Alzheimer?s Coordinating Center (NACC), and centers of excellence in metabolomics, metagenomics, informatics, machine and deep learning. In this proposal we seek to: 1) define compositional and functional changes in the gut microbiome across stages of AD; 2) define metabolome differences in blood and feces related to gut microbiome composition and function and link these to cognitive and brain imaging changes; and 3) connect blood and brain metabolomes to define biochemical and immune axes of gut-brain communication. We will also explore the role of the gut microbiome in the development of neuropsychiatric symptoms (e.g., depressive phenotypes and sleep disturbances). The metabolic state of the brain in health and in disease seems dependent on peripheral metabolic states with influences from gut metabolism. Hence, understanding how peripheral and central metabolism is connected and linked to failures in AD is critical to the understanding of disease pathogenesis and for development of new effective therapies to slow or prevent the disease.